For now, there is no therapy besides hematopoietic cell transplantation with as impressive a track record for relapsed/refractory follicular lymphoma, and we should not ignore that when recommending treatments to our patients.
—Timothy S. Fenske, MD
Follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma (NHL) in the United States. Of the nearly 70,000 new cases of NHL anticipated in 2013,1 approximately 7,000 to 13,000 (10%–19%) will be follicular lymphoma, by recent estimates.2-5 For many years, the median overall survival of patients with follicular lymphoma was 10 years. However, since the introduction of rituximab (Rituxan) and radioimmunotherapy, the survival of patients with follicular lymphoma has significantly improved.6,7
More recently, the addition of rituximab as a maintenance therapy has improved progression-free survival after first-line therapy.8 With ongoing efforts to develop more effective front-line therapies, incorporating agents such as bendamustine (Treanda) and bortezomib (Velcade), there is hope for even further improvement.9
For patients with relapsed/refractory follicular lymphoma, outcomes are not nearly as favorable. Using various regimens such as rituximab, bortezomib/rituximab, bendamustine, bendamustine/bortezomib/rituximab, or radioimmunotherapy, the median progression-free survival in several important studies of relapsed/refractory follicular lymphoma has generally been in the vicinity of 1 year.10-15 In some older studies of rituximab-naive patients, results were more favorable, but today nearly all relapsed/refractory follicular lymphoma patients have had some prior exposure to rituximab. Many will even have rituximab-resistant disease at the time of relapse or progression.
Autologous hematopoietic cell transplantation has been utilized in follicular lymphoma for decades. While autologous hematopoietic cell transplantation is not currently recommended as consolidation of first remission for follicular lymphoma, the situation is quite different for those with relapsed/refractory follicular lymphoma.
One prospective randomized trial in relapsed/refractory disease showed a clear benefit in progression-free survival and a nearly significant improvement in overall survival in favor of autologous hematopoietic cell transplantation vs standard chemotherapy alone.16 In that study, the standard therapy arm had a median progression-free survival of about 1 year, and the autologous hematopoietic cell transplantation arms had a median progression-free survival in excess of 4 years.
Several single-center and multicenter retrospective studies have evaluated autologous hematopoietic cell transplantation for follicular lymphoma. Eight studies of more than 100 patients have been published since 2003; they collectively include over 2,500 patients.17,31 In most of these studies, the progression-free survival curve shows a plateau at around 5 years, with 30% to 50% of patients achieving long-term (5- to 15-year) remissions.
In the three most recent studies, progression-free survival was in the 48% to 56% range at 3 to 5 years.18,19,31 Importantly, in the National Comprehensive Cancer Network (NCCN) study by Evens et al, results were similar in an analysis restricted to patients who had prior rituximab exposure.18 The range of treatment-related mortality in the eight studies since 2003 was 2% to 14%, but only 2% to 3% in the three most recent studies.
While treatment-related myelodysplastic syndromes and acute myeloid leukemia can occur after autologous hematopoietic cell transplantation for follicular lymphoma, the risk is relatively low: 3% to 8% at 5 to 15 years post-transplant using conditioning regimens that do not employ total-body irradiation.20 Importantly, three separate studies suggest improved survival for follicular lymphoma patients who undergo autologous hematopoietic cell transplantation in second or third remission, vs later in the disease course, indicating that early referral for transplantation consideration is prudent.18,21,22
With allogeneic hematopoietic cell transplantation, recent results are also quite encouraging. A shift has occurred such that the majority of allogeneic hematopoietic cell transplantation procedures now performed utilize nonablative or reduced-intensity conditioning regimens. Results from five recent studies, including one multicenter study, show that treatment-related mortality with reduced-intensity conditioning is now in the 8% to 17% range at 1 year. In addition, progression-free survival in these studies was in the 57% to 85% range with median follow-up between 3 and 11 years.23-26,31
Given the low treatment-related mortality, favorable rates of long-term remission, and better results than expected with conventional therapy, one might expect that hematopoietic cell transplantation would be commonly utilized for follicular lymphoma. However, this is not the case.
According to a recent analysis of the National LymphoCare Study, fewer than 3% of patients undergoing second-line therapy for follicular lymphoma were treated with a strategy that included hematopoietic cell transplantation.27 Even if one assumes that only 30% to 50% of patients considered for second-line therapy would be hematopoietic cell transplantation candidates, this would still indicate that 10% or fewer of potential hematopoietic cell transplantation candidates are referred to a transplant center during second-line therapy.
Similarly, data from the Center for International Blood and Marrow Transplant Research (CIBMTR) shows that over the past 10 years, approximately 370 hematopoietic cell transplantations occur in the United States for follicular lymphoma each year (240 autologous and 130 allogeneic hematopoietic cell transplantations).28,29 Assuming that only 80% of U.S. hematopoietic cell transplantations are captured by the CIBMTR (a conservative estimate), as many as 460 to 470 patients may actually undergo hematopoietic cell transplantation yearly.
Now, let’s assume there are about 10,000 new cases of follicular lymphoma in the United States each year.1-5
Since the median age at diagnosis is 63, let’s further assume that about 40% of follicular lymphoma patients will, by the time they need second- or third-line therapy, remain candidates for hematopoietic cell transplantation by age alone.
Let’s further assume that 40% of these age-eligible patients will be found to be poor transplant candidates (due to comorbid conditions, or problems with stem cell collection and/or donor availability). This leaves approximately 2,400 follicular lymphoma patients each year who should be hematopoietic cell transplantation candidates. Yet, the number who actually undergo transplantation is less than 20% of that figure.
So, how can we explain the relatively low use of hematopoietic cell transplantation in follicular lymphoma? There are several potential explanations. In a general sense, (a) patients may be referred but then be found to be poor transplantation candidates, (b) patients may decline transplantation, or (c) patients may not be referred for transplantation evaluation at all.
In scenarios (a) and (b), the dropout occurs predominantly at the transplant center after an initial evaluation. We certainly have patients like this at our center. In my experience, however, this occurs very infrequently. It seems likely that the major factor is that patients are not being referred in the first place.
Why might this be? As a physician working at a transplant center, I cannot be sure. My suspicion is that many community oncologists are reluctant to refer patients for hematopoietic cell transplantation evaluation. In rare cases, this may stem from a concern about potentially losing a patient to the tertiary care center. However, among the community oncologists that I know and collaborate with, I sense a deep commitment to doing what is best for the patient.
So why are patients not referred? I believe that, for many community oncologists, their primary exposure to hematopoietic cell transplantation was during fellowship training. These experiences tended to be heavily weighted toward inpatient work, which involved dealing with patients suffering from complications of transplantation.
In some cases, this exposure occurred in an era when our ability to prevent and treat complications was more limited. They saw many fewer patients doing well after hematopoietic cell transplantation, since those patients spend much less time as inpatients. This experience, consciously or subconsciously, may lead to a perception that hematopoietic cell transplantation should be a treatment of “last resort,” and, in turn, to a reluctance to refer until late in the disease course.
Additionally, depending on where or when they trained, a practicing community oncologist may not have witnessed the important strides made in hematopoietic cell transplantation in the past 10 to 15 years, including less toxic conditioning regimens, more effective stem cell mobilization techniques, high-resolution HLA typing, and breakthroughs in supportive care. These developments, collectively, have led to a decrease in treatment-related mortality after both autologous and allogeneic hematopoietic cell transplantation, and an ability to offer transplantation to a much wider range of patients.
At the same time, the past 15 years have seen an ever-expanding arsenal of non-transplant therapies for lymphoma such as rituximab, bendamustine, radioimmunotherapy, bortezomib, lenalidomide (Revlimid), and emerging agents such as the Bruton’s tyrosine kinase inhibitors, PI3-kinase inhibitors, mTOR inhibitors, new monoclonal antibodies, and antibody-drug conjugates. The availability of multiple nontransplant therapies makes it easier to put off the transplant referral. Many of these nontransplant therapies are marketed aggressively. Hematopoietic cell transplantation does not get marketed in the same way and so may not come to mind as readily when considering treatment options.
Another possible reason for patients not being referred for hematopoietic cell transplantation is that transplant studies are often criticized for being subject to patient selection bias. It is certainly true that retrospective studies and single-arm phase II trials are subject to bias, especially when comparing across trials or using historical controls. I fully agree that we need more high-quality prospective randomized phase III trials evaluating hematopoietic cell transplantation in various settings.
So one may pessimistically look at the transplantation studies I have cited above and think, “patient selection bias.” My response would be, “Send us the patients, and let us select!”
Transplant physicians spend their days trying to identify those patients most likely to benefit from, and least likely to be harmed by, a transplant procedure. Whatever thought process went into selecting patients for the studies cited above, a very similar thought process will be applied to the patients you send to a transplant center. After a discussion of the risks and benefits, I believe that many follicular lymphoma patients would be pleased to be “selected” to have a treatment that gives them the best chance for long-term remission and survival.
Those of us who work in transplant centers should strive to ensure that graduating hematology/oncology fellows have a balanced exposure to hematopoietic cell transplantation. We should also make a stronger effort to keep our community oncology colleagues informed of the advances and current state of our field, so that patients can be offered all options available, including hematopoietic cell transplantation.
Currently, based on available evidence, I recommend that follicular lymphoma patients under age 70, in first or second relapse, be referred for a transplant evaluation. Comorbidity can now be quantified using the well-validated Hematopoietic Cell Transplant Comorbidity Index (HCT-CI). Patients with an HCT-CI score of 3 or higher have increased risk of treatment-related mortality30 and may be found to be poor transplant candidates.
As new, more “targeted” therapies become available, the role of hematopoietic cell transplantation may evolve. However, despite the great enthusiasm for new and emerging agents in follicular lymphoma, their ability to produce long-term remission remains uncertain. For now, there is no therapy besides hematopoietic cell transplantation with as impressive a track record for relapsed/refractory follicular lymphoma, and we should not ignore that when recommending treatments to our patients. ■
Dr. Fenske is Associate Professor of Medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin, Milwaukee.
Disclosure: Dr. Fenske reported no potential conflicts of interest.
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